المنهج الكامل - PowerPoint Presentation

Slide1

المنهج الكامل Slide2

عدد

فقرات

الاختبار

20 فقرة , اختيار متعدد , خمس درجات

مدة الاختبار نصف ساعة

المتغيب عن الاختبار سوف يختبر اختبار مقالي Slide3

Introduction

and CNS

stimulants

Mohammed A. Alyami Head Teaching AssistantDepartment of Pharmacology & ToxicologyCollege of PharmacyKSU

E-mail :

maalyami@ksu.edu.sa

Slide4

Lab Animals will

be used in PHL 322, 326

Mouse

Rat

Frog Slide5

Restraint of mouse

Tail

Restraint Used for : transferring animals from cage to cage.B. Scruff Restraint Used for : Injections

blood withdrawal.Intraperitoneal Injections ( IP )- Restrain the mouse by the scruff method.

Injection Slide6

CNS stimulant drugs

Lab# 1Slide7

Neuron

They are the basic functional units of the nervous system. - They contain three major parts

1- Cell Body 2- Dendrites3- Axons1

23

Axon terminal

Effector

Synapse

Is the site where the axon of a neuron communicates with effectors or other neurons. Slide8

Neurotransmitter

Neurotransmitter

Aspartic acid Excitatory NeurotransmitterGlutamic acid

Excitatory NeurotransmitterGABAinhibitory NeurotransmitterGlycine

inhibitory NeurotransmitterSlide9

CNS stimulants

Definition:

“Stimulants are substances which tend to increase behavioral activity when administered”Signs and symptoms of CNS stimulation : 1- Elevate Mood.2- Increase Motor Activity.3- Increase Alertness.4- Decrease need for Sleep.Slide10

1- Amphetamine 

MOA:

Block the reuptake of Norepinephrine and Dopamine into the presynaptic neuron and increase the release of these Monoamines into the extraneuronal space.  Clinical use:1. Narcolepsy.2. Attention-deficit hyperactivity disorder (ADHD)3. Simple obesity Slide11

Signs and Symptoms:

After injecting

the mice with Amphetamine, you will notice: 1- Hair erection.2- Licking, gnawing.3- Stereotype.4- Sniffing. Slide12

2-

Picrotoxin

  MOA:Non-competitive antagonist of GABA receptors.After injecting the mice with Picrotoxin, you will notice: Clonic Convulsion characterized by :  

1. Asymmetric2. Intermittent3. Spontaneous 4. CoordinatedSlide13

3- Strychnine

MOA:Competitive antagonist of the Glycine receptors. After injecting the mice with Strychnine, you will notice: Tonic convulsion characterized by : 1. Symmetric

2. Reflex in origin3. Continuous 4. Uncoordinated.Slide14

Drug

MOA

Site of action

Signs and symptoms Amphetamine

Blocking the neurotransmitters

’

reuptake and

Promoting the release of neurotransmitters

Cerebral Stimulants

1- Hair erection.

2- Licking, gnawing.

3- Stereotype.

4- Sniffing.

Picrotoxin

antagonist of GABA receptors

Medullary Stimulants

Clonic

Convulsion

characterized by

1. Asymmetric

2. Intermittent

3. Spontaneous

4. Coordinated

Strychnine

Competitive antagonist of the

Glycine receptors

Spinal Stimulants

Tonic convulsion

characterized

by :

1. Symmetric

2. Reflex in origin

3. Continuous

4. UncoordinatedSlide15

CNS depressants

LAB 2Slide16

A

stimulant

is a drug that speeds up activities of the CNSA depressant is a drug that slows brain and body reactionsStimulants increase Depressants decrease

Heart rate

Blood pressure

Respiratory rate

Relax muscle tension

Lower alertness

Cause drowsiness

Increase Motor Activity

.

Increase Alertness.

Decrease need for

SleepSlide17

GABA

Is inhibitory neurotransmitter.

Ligand-gated ion channel

(ionotropic receptors)Metabotropic receptors Slide18

Hyperpolarization of membrane

Ci

-

Ci

-

Ci

-

Ci

-

Ci

-

Ci

-

Ci

-

Ci

-

↑

Cl

- conductance

GABA

A

( Chloride ion channel)

Prevent action potential Slide19

MOA of

Inhaled anesthetics

, barbiturates, benzodiazepines, etomidate, and propofol are facilitate GABA-mediated inhibition at GABAA receptors.Its antagonism of the action of glutamic acid on the NMDA receptor

General Anesthesia Slide20

Sedative-Hypnotic Drugs

Sedation : reduction of anxiety

Hypnosis : induction of sleep Sedative = anxiolytic = antianxiety = minor tranquilizer : a drug that reduce anxiety Increase the dose of sedative that will lead to hypnosisClinical use of Sedative-Hypnotic Drugs AnxietySleep disorder Antiseizure Anesthesia protocol Slide21
Slide22

Tranquilizer

Major tranquilizer = Antipsychotic

Example Chlorpromazine (CPZ)MOA : Work by blocking dopamine (D 2 )receptor.Slide23

Work lab

To demonstrate the effect of different types of CNS depressants as :

- Hypnotics. Phenobarbital - Sedatives. Chloral hydrate (at sedative dose) - Tranquilizers. CPZ    

To learn how to distinguish between their signs if they are given as unknown drugs.Slide24

Righting reflex

If it’s lost Righting reflex ------- -

ve

If it isn’t lost Righting reflex ------- +verighting reflex

  the ability of the mice to assume an optimal position when there has been a departure from it.Is widely used to screen compounds with sedative propertiesSlide25

1- Phenobarbital

Hypnotic drug

After injection of Phenobarbital we can observe :Loss of righting reflex ( -ve)

2- chloral hydrate

Sedative drug

When

the dose

increased

they will induce

sleep.

After

injection of

chloral hydrate

we

can observe :

NO loss righting reflex (+

ve

)Slide26

CPZ

After injection of CPZ we can observe signs such as

:No loss of righting reflex (+ ve) Ataxic gait: loss of muscle coordination .Catalepsy : rigid bodyCreeping gait

Grasping test (CPZ): When you trying to put the mice on the cord, the mice will fall downSlide27

Pain

Lab #3

Analgesic Slide28

Sensory or afferent neurons

Neurons carrying impulses (AP) from

sensory receptor (at PNS) to the CNS

Unipolar neuron

carrying

impulses

AP

Cell body

Spinal cordSlide29

Sensory or Afferent Type

C

fibersNon- myelinatedLow conducting velocityCause

a dull burning painCause non-localized painA fibers

Myelinated High conduction velocity Cause a sharp pain

Cause localized pain

Sensory Receptor

Pain receptor

(

Nociceptors

)

are cells nerve ending that

initiate the sensation of

pain

This process, called nociception

Can be activated by :

Chemical stimuli

Thermal stimuli

Mechanical

stimuli

Noxious Stimuli

An

actually or potentially tissue damaging eventSlide30

cell membrane phospholipids

Arachidonic

acid

COX-2

phospholipases A

2

Prostaglandin E

2

(

PGE

2

)

Sensitizes

nociceptors

to

bradykinin

(BK) , ((the most potent pain producing chemical)) and other pain mediators like substance P histamine, 5-HT…etc.

For

stimulation

nociceptors

, and lead to production of AP

Noxious Stimuli

Release

of endogenous

opioid

peptide

( endorphin)

which cause

inhibiting of nociceptive impulse(

Modulation

)

Then

transmission

the impulse to spinal cord and cortex (

perception

)

-Slide31

Analgesia

Without

Pain

Analgesics Are medicines or drugs that relieve pain (analgesia).

Pain killer Slide32

Opioid

Analgesics

Opium Contains many alkaloids

morphineOpiate : A drug derived from alkaloids of the opium

Opioid : the class of drugs that includes opiate, and all synthetic and semisynthetic drugs that mimic the action of opiate

Agonists

Mixed agonist- antagonists

e.g.

nalbuphine

Antagonists

e.g. Naloxone

Strong:

morphine

Moderate :

codeine

weak:

propoxyphene

Interaction with opioid receptor Slide33

opioid receptor

It’s G protein-coupled receptor.

Three types 1- μ (mu) Most of the analgesic opioids are μ-receptor agonistsResponsible for some major unwanted effects (e.g. respiratory depression, euphoria, sedation and dependence) 2- κ (kappa) 3- δ (delta) Slide34

Non Opioid Analgesics

NSAIDs

Non- SteroidalDrugs

Anti-Inflammatory

Arachidonic

acid

COX-2

COX-1

Prostaglandins

Thromboxane

Prostacyclin

NSAID

NSAID

-

-Slide35

Cox non-selective inhibitors

Cox-2 selective inhibitor

(coxib) Example : Aspirin,Ibuprofen,Diclofenac…etc

Example Celecoxib

Thrombosis

GI ulcer Slide36

LAB WORK

Objective :

To show the analgesic effects of different analgesics using different methods. Writhing test.Hot plate method.Slide37

Procedure:

4.Compare the number of writhing for each drug and comment on the results:

A drug has less number of writhing that has more potency as analgesic.

Drug

No. of writhing/20 minutes

Control

Acetic cid

Test 1

Morphine acetic acid

Test 2

Aspirin acetic acid

5 min’s

5 min’sSlide38

Hot plate method

principle:

The paws of the mouse are very sensitive to heat at temperature which are not damaging the skin . At temperature of 55 C the mouse will jump and licking the paws. The time till these response occur is calculated and is prolonged after administration of analgesics.

Hot Plate Analgesia Meter Slide39

Inflammation

It

is a reaction of living tissue to an injury.

Acute Chronic

Rapid onset , Short duration

Gradual onset ,

long duration

Cardinal

signs of acute

inflammation:

Redness

Hotness

Swelling

Pain

and

tenderness

Types Slide40

Mediator

Main activity

Histamine

Vasodilation, increase permeability

Prostaglandins ( PGs )

Vasodilation,

pain,

fever

Leukotrienes

(LKs)

Increase permeability

Bradykinin

Vasodilation,

increase permeability,

pain

Inflammatory Mediators Slide41

Inflammatory process (( vascular phase))

Tissues damage

Release inflammatory mediators

Histamine

PGE2

LKs

Bradykinin

Vasodilation (V.D.)

Increase blood flow

Increase vascular permeability lead to formation of fluid

exudate((plasma protein))

Edema FormationSlide42

Aiming of the inflammation response

prevents the spread of damaging agents to nearby tissues,

disposes of cell debris and pathogens, andsets the stage for repair. Inflammatory process Cardinal signs of acute inflammation: Redness: due to Vasodilation Hotness: due to Vasodilation and increase blood flow

Swelling: due to vascular leakage Pain and tenderness: due to irritation by chemical mediators and pressure of swelling Slide43

Anti-inflammatory drugs

Steroidal

Non-steroidal

GlucocorticoidsNSAIDs like Aspirin aspirin

Containing steroid

moiety

don’t contain steroid moietySlide44

Secreted glucocorticoids from adrenal cortex

Adrenal gland

glucocorticoids : are steroids hormones which include cortisone and cortisol (also called hydrocortisone) cortisol : is predominant glucocorticoids in human Slide45

Glucocorticoids

Natural

Cortisol

Cortisone Synthetics Prednisone DexamethasoneOne of the MOA They act by indirect inhibition of the enzyme phospholipase A2 by induce

synthesis of a protein “lipocortin-1” which has the inhibitory effect on phospholipase A2.Some Adverse Effects Hyperglycemia

Osteoporosis

Moon face,

buffalo

hump

Clinical uses

A- adrenal disorders: like Addison's disease

B-

Nonadrenal

disorders :

Anti-inflammatory for treatment asthma as example

Immunosuppression: to prevent organ transplant rejection

…..etc. Slide46

NSAIDs

Non- Steroidal

Drugs

Anti-Inflammatory

Cox non-selective inhibitors

Cox-2 selective inhibitor

(

coxib

)

Example :

Aspirin,

Ibuprofen,

Diclofenac

…

etc

Example

Celecoxib

((has a FDA initiated “black box” warning concerning cardiovascular risk))

MOA

Inhibit synthesis of PGs through inhibition of

COXSlide47

glucocorticoids

NSAID

Containing steroid moiety in their structure They don’t contain steroid moietyPowerful anti-inflammatory , immunosuppression, adrenal disorder

anti-inflammatory, analgesic, antipyretic anti-platelet ((only aspirin)) Prevent synthesis of LKs and PGs Prevent synthesis of PGs

Treatment of asthma Can be caused asthma

Compare between Glucocorticoids &NSAID Slide48

Measurement the activity of

anti-inflammatory

drugs

Method : Paw Oedema Method

Principle

:

Induction

a chemical

inflammation by

injecting an

irritant

(

formalin

) into

rat’s

paw

Objective

:

Measure

the anti-inflammatory activity

of

aspirin

and hydrocortisone (cortisol)

with

different

doses

Equipment

:

PlethysmometerSlide49

Procedure :

1- select 5 rats

2- inject each rat 1 ml urethane for anesthesia.3- select one as control and inject the rest of them Intraperitoneal (IP) rat 1 >>> control rat 2 >>> 40 mg/kg aspirin rat 3 >>> 80 mg/kg aspirin rat 4 >>> 20 mg/kg hydrocortisone

rat 5 >>> 40 mg/kg hydrocortisone4- after 1 hr. , inject 0.1 ml formalin in each rat

into

their paws >>>

to induce inflammation

.

5- after 1

hr.

, take the reading using the

plethysmometer

of each

rat paw ( right and left

).

6- calculate the inflammation and response % for each drug. Slide50

Response%

inflammation

RP

LP

Dose

----------

C

control

T1

40 mg/kg asp.

T2

80 mg/kg asp.

T3

20 mg/kg hydro.

T4

40 mg/kg hydro.

Inflammation =

LP

-

RP

Response %

 Slide51

Response

% Anti-inflammatory

activity

Response%

inflammation

RP

LP

Dose

---------

0.53

1.02

1.55

control

37.74

0.33

1.2

1.53

40 mg/kg asp.

69.81

0.16

1.25

1.41

40 mg/kg hydro.

Inflammation for

Control ((

C

)) : 1.55-1.02 =

0.53

Asprirn

: 1.53- 1.2 =

0.33

Hydrocortisone : 1.41-1.25 =

0.16

Inflammation =

LP

-

RP

Response %

Response % of aspirin

Response % of hydro.

 Slide52

Local Anesthetics

Lab# 5

PHL 322

PHL 326Slide53

Local Anesthesia

Local Anesthetic

(LA)

Is the

condition

that results when sensory transmission (action potential) from a local area of the body to the CNS is

blockade

Is a

drug

that causes reversible local anesthesia and a loss of nociception.

Caused

Block nerve conduction of sensory impulse Slide54

LAs

block

voltage-dependent sodium channels (at axon) and reduce the influx of sodium ions, thereby preventing depolarization of the membrane

and blocking conduction of the action potential.MOASlide55

The commonly used LA are

weak base

with at least 1 ionizable amine function that can become charged through the gain of a proton. Drug+

+H+

Drug

-H

H

+

+H

+

-H

Ionizable

amine

the ionize (charged) form

The

Nonionize

(

uncharged) form

More lipid soluble

It

will facilitate its penetration through the cell

membrane (bilayer phospholipid)

Once the drug has penetrated the lipid barrier and reach its site of

action (receptor)

it ionized and the ionized form is responsible for LA activitySlide56

Drug

+

Drug

+

Drug

+H+

-H+

Na+ channel

Receptor

Drug

Drug

+H+

-H+

Drug

+

Inside

Outside

Membrane

Membrane diffusion

Na+

Na+Slide57

PH

C

harged forms

Acidosis

Acidosis such as caused by inflammation at a wound partly reduces the action of

LAs.

This is partly because most of the anesthetic is ionized and therefore unable to cross the cell

membrane.Slide58
Slide59

Local Anesthesia (including analgesia)

Paralysis

(

no clinical application) Antiarrthymia(e.g. Lodicaine)

Clinical use Slide60

Definition

Method of

adm. application LA to the surface of the skin or mucosaSurface anesthesia Can be called “

Topical anesthesia” : gel, spray, ointment injected of LA into the epidural space

where it acts primarily on the spinal nerve rootsepidural anesthesia injected LA into the cerebrospinal fluid

, usually at the lower back, where it acts on spinal nerve roots and part of the spinal cord.

Spinal anesthesia

Method of administration Slide61

Many shorter acting local anesthetics are readily absorbed into the blood from the injection site after administration.

Decrease of duration

Increase in systemic toxicity

This can be accomplished by administration of a vasoconstrictor (usually an agonist sympathomimetic like epinephrine ) with the local anesthetic agent.

blood flow to the area is reduced

Epinephrine decrease of rate of absorption in blood that leads to minimize of systemic toxicity and increase duration . Slide62

Treatment of toxicity

Severe toxicity is treated

symptomatically; there are no antidotes. e.g. Convulsions are usually managed with intravenous diazepam or a short-acting barbiturate such as thiopental.Slide63

Frog

’

s plexus method“Foot withdrawal reflex of frog”Principle:The skin of the frog is very sensitive to diluted HCL and will reflex by withdrawing its leg when immersed in HCLSlide64

Administer

1 ml of LA solution in the abdominal sac of the frog and observe the zero time.

Test the withdrawal reflex at 3 minutes interval and wash with tap water after each exposure to the acid, observe the time at which the absence of withdrawal reflex occursOnset time: is the time from adding LA until the acid fails to provoke withdrawal of the footTabulate your results and determine which of LA is more rapid in its action than the other.LA

The time interval 3691215

1821

Still withdrawal Reflex

Still

withdrawal

Reflex

Absence of

withdrawal Reflex

the drug has activity and blocks sodium

channels

((

Onset

time))Slide65

Lignocaine

Procaine

The time interval

-

-

3

+

-

6

-

9

-

12

-

15

+

18

Negative (-)=

means the presence of the withdrawal reflex (the drug has

no activity

).

Positive (+)=

means the absence of the withdrawal reflex (the drug has

activity

and blocks sodium channels)

Conclusion:

From the table we conclude that

lignocaine

is more rapid in inducing local anesthesia

(( rapid onset))

than

procaine